ADCY5-Related Movement Disorder

Excerpt

Clinical characteristics: ADCY5-related movement disorder (ADCY5-MD) encompasses a broad spectrum of continuous and/or paroxysmal hyperkinetic involuntary movements, the most common of which are generalized chorea, generalized dystonia, and/or generalized or segmental myoclonus. At the mild end of the spectrum, affected individuals may maintain overall motor development and remain ambulatory; however, fine motor skills may be affected by involuntary movements. At the severe end of the spectrum, affected individuals may have early-onset hyperkinetic movements with significant disability and global developmental delay. Intrafamilial variability has also been demonstrated in one multigenerational family in which a mildly affected parent had much more severely affected children with disease onset in early childhood.

Diagnosis/testing: The diagnosis of ADCY5-MD is established in most probands by identification of a heterozygous pathogenic variant in ADCY5 by molecular genetic testing (autosomal dominant ADCY5-MD); rarely, the diagnosis is established in a proband by identification of biallelic pathogenic variants in ADCY5 by molecular genetic testing (autosomal recessive ADCY5-MD).

Management: Treatment of manifestations: Multidisciplinary care by specialists in movement disorders for consideration of treatment options; speech-language therapy for dysarthria; occupational therapy, speech-language therapy, and nutritional support for feeding issues; management of manifestations of GI dysmotility (e.g., GERD and constipation) by gastroenterologist; orthopedics, physical medicine and rehabilitation, and physical/occupational therapy to maintain mobility and function; management of neurobehavioral/psychiatric manifestations by mental health professionals.

Surveillance: Routinely scheduled visits with treating clinicians to monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations.

Pregnancy management: Potential teratogenic effects of medications given for treatment of ADCY5-MD should be discussed with affected women of childbearing age, ideally prior to conception.

Genetic counseling: ADCY5-MD is typically inherited in an autosomal dominant manner. Autosomal recessive inheritance of ADCY5-MD has been reported in eight individuals (from five families) to date.

Autosomal dominant inheritance: The majority of individuals have the disorder as the result of a de novo heterozygous constitutional or mosaic (postzygotic) pathogenic variant; some individuals have the disorder as the result of a pathogenic variant inherited from a parent who may or may not have clinical manifestations of the disorder. Each child of an individual with a constitutional ADCY5 pathogenic variant has a 50% chance of inheriting the pathogenic variant. Each child of an individual with a mosaic ADCY5 pathogenic variant has up to a 50% chance of inheriting the pathogenic variant (offspring who inherit a pathogenic variant from a proband with mosaic ADCY5-MD will have a constitutional pathogenic variant and consequently may be more severely affected than the proband).

Autosomal recessive inheritance: If both parents are known to be heterozygous for an ADCY5 pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being heterozygous, and a 25% chance of inheriting neither of the familial ADCY5 pathogenic variants. Heterozygous sibs of a proband with autosomal recessive ADCY5-MD are asymptomatic and are not at risk of developing the disorder.

Once the ADCY5 pathogenic variant(s) have been identified in an affected family member, prenatal and preimplantation genetic testing for ADCY5-MD are possible.